It has been shown that injection of opiates into the nucleus accumbens of the rat produces amphetamine-like behavioral activation, and that rats will self-administer morphine directly into this brain region. Recent unpublished studies by the Principal Investigator and others (Dr. Louis Stinus, Bordeaux, France; personal communication) have demonstrated that destruction of the mesolimbic dopamine system with 6-hydroxy-dopamine produces supersensitivity to the behavioral activation caused by microinjection of D-Ala-Met-enkephalinamide into the nucleus accumbens. Thus, depletion of dopamine in the nucleus accumbens produces behavioral supersensitivity to both dopamine and enkephalin. The purpose of this proposal is to characterize this phenomenon behaviorally and neurochemically. D-Ala-Met-enkephalinamide will be microinjected into the nucleus accumbens of rats having the mesolimbic dopamine system compromised by one of the following pretreatments; 6-hydroxydopamine, electrolytic or kainic acid lesions, chronic reserpine treatment or chronic neuroleptic treatment. Changes in locomotion and rearing will be measured. In addition, effects of these lesions, etc. on catecholamine and met-enkephalin levels in the nucleus accumbens and striatum shall be determined with HPLC and electrochemical detection. Finally, changes in opiate receptors will be assessed. Any interaction between enkephalin systems and the mesolimbic dopamine system may be useful in our understanding of schizophrenia. More specifically, if chronic neuroleptic treatment can alter the behavioral response to intra-accumbens injection of enkephalin, patients maintained on chronic neuroleptics may have enhanced responses to some behavioral effects of opiates. The reinforcing effect of opiate injection into the nucleus accumbens supports a potential interaction between a compromised mesolimbic dopamine system and the abuse potential of opiates.